Diagnosis of Pancreatic Ductal Adenocarcinoma by Immuno-Positron Emission Tomography

Abstract

Diagnosis of pancreatic ductal adenocarcinoma (PDAC) by current imaging techniques is useful and widely used in the clinic but presents several limitations and challenges, especially in small lesions that frequently cause radiological tumors infra-staging, false-positive diagnosis of metastatic tumor recurrence, and common occult micro-metastatic disease. The revolution in cancer multi-"omics" and bioinformatics has uncovered clinically relevant alterations in PDAC that still need to be integrated into patients' clinical management, urging the development of non-invasive imaging techniques against principal biomarkers to assess and incorporate this information into the clinical practice. "Immuno-PET" merges the high target selectivity and specificity of antibodies and engineered fragments toward a given tumor cell surface marker with the high spatial resolution, sensitivity, and quantitative capabilities of positron emission tomography (PET) imaging techniques. In this review, we detail and provide examples of the clinical limitations of current imaging techniques for diagnosing PDAC. Furthermore, we define the different components of immuno-PET and summarize the existing applications of this technique in PDAC. The development of novel immuno-PET methods will make it possible to conduct the non-invasive diagnosis and monitoring of patients over time using in vivo, integrated, quantifiable, 3D, whole body immunohistochemistry working like a "virtual biopsy".

Keywords: PDAC; diagnostic imaging; immuno-PET; pancreatic cancer.

Figure 1

Cases of radiologically infra-staged and false-positive diagnosis of metastatic tumor recurrence by current imaging methods. (A,B) A radiologically infra-staged T2 N0 pancreatic ductal adenocarcinoma (PDAC) was found to be a locally advanced pT4 pN1 PDAC in the pathology report. (A) magnetic resonance imaging (MRI) showing a small cystic area in the pancreas’ uncinate process (green arrow), a bile duct stricture, no direct signs of malignancy. (B) A computed tomography (CT) performed after bile stent placement showed a small hypodensity (red arrow) next to the superior mesenteric artery. (C,D) A case of a false-positive diagnosis of metastatic tumor recurrence. (C) Some months after surgical excision of a PDAC stage pT2 pN0 M0 R0, an asymptomatic solid mass in the left costal wall (yellow arrow) was shown by a CT scan. (D) An 10.43 SUVmax in 2-[18F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) positron emission tomography (PET)-CT was suspicious of a PDAC metastatic relapse. A tumor core biopsy found inflammatory and fibrotic tissue but no sign of malignant cells.

Figure 2

Occult micro-metastatic disease is common in PDAC, often undetected by current radiology techniques. Case. (A) At the time of diagnosis, a CT found 37 mm pancreatic head tumor (yellow arrows) contacting > 50% with the superior mesenteric vein (white arrow) with no liver metastasis (B) and classified as a resectable stage T3 N0 M0. In a CT performed just 4 weeks after the basal one, the pancreatic mass was stable (yellow arrows) (C), but liver metastases were found (red arrow) (D), the tumor re-staged as a T3 N0 M1, and the tumor surgical excision was not indicated anymore.

Figure 3

Local inflammatory and fibrotic changes at the surgical site and treatment response evaluation are diagnostics challenge for radiologists. (A–D) A case of local inflammatory and fibrotic changes at the surgical site are a diagnostic challenge for radiologists. A PDAC was suspected because of a bile duct stricture (A) (yellow arrow). The tumor was surgically resected; the pathology report showed a stage I cancer, pT1c pN0 M0 R1 (retroperitoneal margin was microscopically affected). Findings in a CT performed two months after surgery required a differential diagnosis between benign fibrotic tissue at the surgical site and a retroperitoneal tumor relapse (red arrows). The increasing tissue size (red arrows) in a consecutive 1-month later performed CT (C) and the moderately high 3.67 SUVmax found in an [¹⁸F]FDG PET–CT (D) finally made the diagnosis of relapsed PDAC, and a palliative combination chemotherapy regimen was initiated. (E,F) [¹⁸F]FDG PET PDAC treatment response evaluation. (E) PDAC relapsed at the surgery site (15 mm, 5.73 SUVmax) (red arrow) and metastatic lymph node in the superior mesenteric vein area (10 mm, 4.0 SUVmax) (white arrow). (F) Early complete metabolic response after two cycles of chemotherapy.

Figure 4

Representation of the three main components of immuno-PET techniques: target, antibodies, and radionuclides. Abbreviations: Ab-Antibody; Fab-Fragment antigen-binding; F(ab’)₂-Fab dimer; scFv- single-chain variable fragment; Nb-Nanobody, ¹⁸F-fluorine; ⁴⁴Sc-scandium; ⁵²Mn-manganese; ⁶⁴Cu-copper; ⁶⁸Ga-gallium; ⁷⁶Br-bromine; ⁸⁶Y-yttrium; ⁸⁹Zr-zirconium; ¹²⁴I-iodine [66,67]. Image generated with BioRender.

Figure 5

ImmunoPET–CT of MT1-MMP metalloproteinase in a preclinical model of PDAC. (A) Coronal, (B) axial, and (C) sagittal views of fused Immuno-PET and CT images of an orthotopic pancreatic patient-derived xenograft mouse. White arrows indicate tumor location. The imaging probe used was [⁸⁹Zr]Zr-DFO-LEM2/15, a mAb developed against the MT1-MMP metalloproteinase [107]. Owing to the central role that this metalloproteinase plays in collagen-induced gemcitabine resistance, this probe could be used for the early prediction of resistance to gemcitabine in metastatic PDAC patients.